Intestinal Alkaline Phosphatase Deficiency Leads to Lipopolysaccharide Desensitization and Faster Weight Gain

Abstract

Animals develop in the presence of complex microbial communities, and early host responses to these microbes can influence key aspects of development, such as maturation of the immune system, in ways that impact adult physiology. We previously showed that the zebrafish intestinal alkaline phosphatase (ALPI) genealpi.1was induced by Gram-negative bacterium-derived lipopolysaccharide (LPS), a process dependent on myeloid differentiation primary response gene 88 (MYD88), and functioned to detoxify LPS and prevent excessive host inflammatory responses to commensal microbiota in the newly colonized intestine. In the present study, we examined whether the regulation and function of ALPI were conserved in mammals. We found that among the mouse ALPI genes,Akp3was specifically upregulated by the microbiota, but through a mechanism independent of LPS or MYD88. We showed that disruption ofAkp3did not significantly affect intestinal inflammatory responses to commensal microbiota or animal susceptibility toYersinia pseudotuberculosisinfection. However, we found thatAkp3−/−mice acquired LPS tolerance during postweaning development, suggesting thatAkp3plays an important role in immune education. Finally, we demonstrated that inhibiting LPS sensing with a mutation inCD14abrogated the accelerated weight gain inAkp3−/−mice receiving a high-fat diet, suggesting that the weight gain is caused by excessive LPS inAkp3−/−mice.